title: Chronic treatment with angiotensin-(1-7) improves renal endothelial dysfunction in apolipoproteinE-deficient mice.
abstract: OBJECTIVE
  ApolipoproteinE-deficient [apoE (-/-)] mice, a model of human atherosclerosis, develop endothelial dysfunction caused by decreased levels of nitric oxide (NO). The endogenous peptide, angiotensin-(1-7) [Ang-(1-7)], acting through its specific GPCR, the Mas receptor, has endothelium-dependent vasodilator properties. Here we have investigated if chronic treatment with Ang-(1-7) improved endothelial dysfunction in apoE (-/-) mice.
  
  
  METHODS
  ApoE (-/-) mice fed on a lipid-rich Western diet were divided into three groups and treated via osmotic minipumps with either saline, Ang-(1-7) (82 µg·kg(-1) ·h(-1) ) or the same dose of Ang-(1-7) together with D-Ala-Ang-(1-7) (125 µg·kg(-1) ·h(-1) ) for 6 weeks. Renal vascular function was assessed in isolated perfused kidneys.
  
  
  RESULTS
  Ang-(1-7)-treated apoE (-/-) mice showed improved renal endothelium-dependent vasorelaxation induced by carbachol and increased renal basal cGMP production, compared with untreated apoE (-/-) mice. Tempol, a reactive oxygen species (ROS) scavenger, improved endothelium-dependent vasorelaxation in kidneys of saline-treated apoE (-/-) mice whereas no effect was observed in Ang-(1-7)-treated mice. Chronic treatment with D-Ala-Ang-(1-7), a specific Mas receptor antagonist, abolished the beneficial effects of Ang-(1-7) on endothelium-dependent vasorelaxation. Renal endothelium-independent vasorelaxation showed no differences between treated and untreated mice. ROS production and expression levels of the NAD(P)H oxidase subunits gp91phox and p47phox were reduced in isolated preglomerular arterioles of Ang-(1-7)-treated mice, compared with untreated mice, whereas eNOS expression was increased.
  
  
  CONCLUSIONS
  Chronic infusion of Ang-(1-7) improved renal endothelial function via Mas receptors, in an experimental model of human cardiovascular disease, by increasing levels of endogenous NO.
authors.affiliation: Department of Nephrology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany. johannes.stegbauer@med.uni-duesseldorf.de
authors.forename: J
authors.initials: J
authors.lastname: Stegbauer
authors.forename: S A
authors.initials: SA
authors.lastname: Potthoff
authors.forename: I
authors.initials: I
authors.lastname: Quack
authors.forename: E
authors.initials: E
authors.lastname: Mergia
authors.forename: T
authors.initials: T
authors.lastname: Clasen
authors.forename: S
authors.initials: S
authors.lastname: Friedrich
authors.forename: O
authors.initials: O
authors.lastname: Vonend
authors.forename: M
authors.initials: M
authors.lastname: Woznowski
authors.forename: E
authors.initials: E
authors.lastname: Königshausen
authors.forename: L
authors.initials: L
authors.lastname: Sellin
authors.forename: L C
authors.initials: LC
authors.lastname: Rump
mesh_terms: D000803:Angiotensin I / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000804:Angiotensin II / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D015918:Infusion Pumps, Implantable; D007668:Kidney / Q000098:blood supply / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010477:Perfusion; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: C092006:7-Ala-angiotensin (1-7); D000959:Antihypertensive Agents; D001057:Apolipoproteins E; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D000804:Angiotensin II; D009569:Nitric Oxide; D000803:Angiotensin I; D006861:Hydrogen Peroxide; D006152:Cyclic GMP; C118790:angiotensin I (1-7)